Project Summary The objective of this proposal is to decipher the mechanisms involved in CD38 signaling in patients with chronic lymphocytic leukemia (CLL, a B-cell cancer); how its increased expression drives an aggressive clinical course and whether its targeted therapeutic disruption can be beneficial for patients. CD38 is expressed on all hematopoietic tissues and functions as both an ecto-enzyme to regulate NAD metabolism and as a co-receptor to amplify signaling through the B-cell receptor (BCR) on B-cells and the T-cell receptor (TCR) on T-cells. Increased CD38 expression on CLL cells is associated with an unfavorable disease course in patients; resulting in shorter overall survival and time to treatment. While the role of CD38 as a negative prognostic marker in CLL has been established for over 2 decades, the therapeutic benefit to be derived by patients from its targeted inhibition, has, till date remained an open-ended subject. Much of this uncertainty has been due to lack of high-affinity, clinical-grade agents that can bind and inhibit CD38; thus, resulting in our inability to study the effects of CD38 disruption on CLL biology. Indeed, with the availability of Daratumumab, (Dara, anti-CD38 mAb, FDA-approved in multiple myeloma), as well as several other anti-CD38 mAbs and small molecule inhibitors in development, this issue will for the first time be appropriately addressed; by our group. Our preliminary data strongly indicates that targeting CD38 has a direct lethal effect on CLL cells, reduces the population of tumor-supportive T-regulatory cells (Tregs) and increases the quantity and functional capacity of tumor-specific CD8+ T-cells. These are novel observations and will be examined through the following aims where we will: 1. Determine the molecular processes of how CD38 activity in CLL cells promotes disease progression. 2. Elucidate the role of CD38 in the suppression of anti-tumor T-cell responses in vitro and in vivo. 3. Evaluate effects of Dara-based therapy in CLL patients on a phase II clinical trial. While the first two aims are highly mechanistic in nature, results from their completion will guide studies in Aim 3, where we will examine changes in CD38 enzymatic/receptorial activity and in the T-cell architecture in patients who are on Dara-based treatment (on an accompanying, but separately funded phase II study). Thus, our long-term goals are to understand the fundamentals of CD38 biology in the tumor cells themselves and in neighboring cells within the tumor microenvironment. Mechanistic insight into the processes engaged upon CD38 inhibition will propel more effective development of anti-CD38 treatments and no doubt lead to a paradigm shift- elevating CD38 from the category of a prognostic marker to a bonafide therapeutic target in CLL.